Novel process for preparation of 10-oxo-10, 11-dihydro-5h-dibenz [b,f] azepine-5-carbox- amide (oxcarbazepine) via intermediate, 10-methoxy-5h-debenz[b,f] azepine-5-carbonyl- chloride

ABSTRACT

A process for preparation of 10-oxo-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide (oxcarbazepine) via intermediate 10-methoxy-5H-dibenz[b,f]azepine-5-carbonyl chloride, comprising the steps: a) Preparation of an intermediate 10-methoxy-5H-dibenz[b,f]azepine-5 carbonyl, chloride from 10-methoxyiminostillbene using bis (trichloromethyl) carbonate (BTC) with organic base such as aliphatic or aromatic tertiary amines in organic solvent; b) Conversion of the intermediate to 10-methoxy-5H-dibenz[b,f]azepine-5-carboxamide using ammonia in organic solvent; c) Formation of oxcarbazepine from step (b) using Bronsted acid in an organic solvent at a temperature between 25° C.-80° C., preferably at 50° C. to 70° C.; and d) Isolation of oxcarbazepine.

FIELD OF THE INVENTION

The present invention relates to an improved process for preparation of10-methoxy-5H-dibenz[b,f]azepine-5-carbonyl chloride from10-methoxy-5H-dibenz[b,f]azepine (10-methoxy iminostilbene) without theuse of phosgene and its further conversion to10-oxo-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide (oxcarbazepine)without the use of strong mineral acids.

BACKGROUND AND PRIOR ART

Oxcarbazepine is an anticonvulsant drug used as an anti-epilepticalagent in treatment of AIDS-related neural disorders and for treatment ofParkinson's disease

Several processes for preparing Oxcarbazepine have been reported.

U.S. Pat. No. 3,462,775 describes the preparation of oxcarbazepine from10-methoxy iminostilbene by phosgenation in toluene, followed byamidation (ethanol and ammonia) and hydrolysis in acidic medium to get edesired product (Scheme 1). The phosgenation is carried out atrelatively high temperatures of around 95° C. and the hydrochloric acidproduced leads to the formation of undesirable impurities. The processuses phosgene gas, which is toxic and hazardous requiring extremeprecaution making this process commercially unattractive.

Canadian Patent 112 241 describes an alternate preparation ofoxcarbazepine from the catalysed re-arrangement of10,11-epoxycarbamazepine, prepared from carbamazepine by reaction withm-chloroperbenzoic acid (CPBA) (Scheme-2). Starting with Carbamazepine,which is an expensive raw material, the conversion to its epoxide ispoor in quality and yield.

EP Patent Application 028028, discloses a process involving nitration of5-cyanoiminostilbene followed by reduction and hydrolysis (Scheme-3).However, the drawback of the process is in the preparation of the5-cyanoiminostilbene itself, which can be made from iminostilbene andcyanogen chloride. The latter is also toxic, hazardous and difficult tohandle.

Swiss Patent No. 642 950 suggests hydrolysis of the10-chloro-5H-dibenz[b,f]azepin-5-carboxamide using concentratedsulphuric acid to form the oxcarbazepine. However the yields are poor.

Further it may be noted that in all the processes disclosed in the priorart discussed above (Scheme 1 and Scheme 3) and U.S. Pat. No. 5,808,058,EP Application 1 302 464 A1 and PCT Publication WO 01156992A2, theconversion of 10-methoxy-5H-dibenz[b,f]azepine-5-carboxamide to10-oxo-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide (oxcarbazepine)is effected using strong mineral acids or mixture of mineral acids andacetic acid in aqueous medium. This leads to degradation ofoxcarbazepine

Methods described in the prior art have severe limitations in terms ofpoor quality and yields and also in some cases with the use of hazardousmaterials such as phosgene that need extreme care during usage makingthem commercially unattractive. Moreover the HCl formed during thecourse of the reaction and the relatively higher temperatures used leadsto formation of undesired impurities.

There is a long standing need in the industry to provide cost effective,safe and easy operative processes for the production of10-methoxy-5H-dibenz[b,f]azepine-5-carbonyl chloride from10-methoxy-5H-dibenz[b,f]azepine (10-methoxy iminostilbene) without theuse of phosgene and its further conversion to10-oxo-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide (oxcarbazepine)without the use of mineral acids.

SUMMARY OF THE INVENTION

The main object of the invention is to provide a cost effective, safeand high yielding process for the production of10-methoxy-5H-dibenz[b,f]azepine-5-carbonyl chloride, from10-methoxy-5H-dibenz[b,f]azepine (10-methoxy iminostilbene) without theuse of phosgene gas as is practiced in the prior art an importantintermediate for the synthesis of10-oxo-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide(oxcarbazepine). It is further an object of the invention to provide aprocess for the conversion of the intermediate10-methoxy-5H-dibenz[b,f]azepine-5-carboxamide to10-oxo-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide (oxcarbazepine)without the use of mineral acids.

Another object of the invention is to develop a process that can becarried out at relatively lower temperatures to avoid the formation ofany undesirable impurities.

Yet another object of the invention is to provide a cost effectiveprocess using easily available raw materials.

Yet another object of the invention is to provide a process for theconversion of the intermediate10-methoxy-5H-dibenz[b,f]azepine-5-carboxamide to10-oxo-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide (oxcarbazepine)using mild reagents such as methane sulphonic acid, para toluenesulphonic acid, Lewis acids, cationic resins, etc.

DETAILED DESCRIPTION OF INVENTION

Thus in accordance of this invention the reaction (scheme 4) comprisessteps

-   -   Preparation of intermediate        10-Methoxy-5H-dibenz[b,f]azepine-5-carbonyl chloride from        10-methoxyiminostilbine using bis-(trichloromethyl) carbonate        (BTC) or triphosgene and an appropriate base in the presence of        an organic solvent.    -   Conversion of 10-Methoxy-5H-dibenz[b,f]azepine-5-carbonyl        chloride to 10-Methoxy-5H-dibenz[b,f]azepine-5-carboxamide using        ammonia in a suitable organic solvent    -   Formation of oxcarbazepine from        10-Methoxy-5H-dibenz[b,f]azepine-5-carboxamide using Lewis acids        in appropriate organic solvent.

10-Methoxyiminostilbene is dissolved in a solvent and cooled below 10°C. and bis-(trichloromethyl) carbonate (BTC) is added. An organic baseis slowly added to the above solution over a period ranging from 3-24hours maintaining the temperature below 10° C. till the reaction goes tocompletion. Optionally on completion of the base addition the reactionmixture is allowed to warm up to around room temperature and maintainedat this temperature till the completion of the reaction as monitored byTLC/HPLC. On completion of the reaction, the reaction mixture isquenched in water and the layers are allowed to separate. The organiclayer is separated and distilled to obtain crude10-methoxy-5H-dibenz[b,f]azepine-5-carbonyl chloride which is purifiedusing an organic solvent.

In the subsequent step 10-Methoxy-5H-dibenz(b,f)azepine-5-carbonylchloride is refluxed in an aprotic solvent and ammonia gas is purgedtill the reaction goes to completion. The solvent is distilled and wateris added, cooled to room temperature to isolate the10-Methoxy-5H-dibenz[b,f]azepine-5-carboxamide.

10-Methoxy-5H-dibenz[b,f]azepine-5-carboxamide is stirred in an organicsolvent in the presence of a Lewis acid at temperature upto 80° C.depending on the solvent used. On completion of the reaction thereaction mixture is cooled to room temperature and the crudeoxcarbazepine is separated and purified.

The solvent used in the carbonyl chloride preparation step may beselected from chlorinated aliphatic hydrocarbons such as methylenedichloride, chloroform, ethylene dichloride, 1,1,1,-trichloroethane,trichloroethylene etc. or aromatic hydrocarbon solvent such as toluene,xylene, chlorobenzene, etc. or aprotic solvents including Dimethylformamide, dimethyl acetamide, N-methyl pyrrolidine and acetonitrile.The organic base used in this step is selected from aliphatic/aromatictertiary amines such as triethyl amine/diethyl aniline, pyridine,picoline etc.

In an embodiment of the process initial addition of the base may befollowed by the addition of BTC.

The time of the addition of base ranges from 3-8 hrs, the temperature atwhich the base is added may range upto 30° C. preferably below 10° C.and most preferably from 0° to +5° C. The reaction period may vary fromabout 3 hours to about 10 hours. The molar ratio of 10-methoxyiminostilbene to BTC is 1:0.34-0.5. The molar ratio of 10-methoxyiminostilbene verses the base is 1:1-1.5.

The solvents preferred in the amidation reaction are selected fromsolvents like acetone, methyl cellosolve, methanol, ethanol, isopropylalcohol, dimethyl formamide, dimethlacetamide, N-methyl pyrrolidone oraromatic solvents like toluene, xylene etc.

The solvent used in the final oxo preparation step ay be selected fromchlorinated aliphatic hydrocarbons such as methylene dichloride,chloroform, ethylene dichloride, 1,1,1,-trichloroethane,trichloroethylene etc or aromatic hydrocarbon solvent such as toluene,xylene, chlorobenzene, etc. or aprotic solvents including dimethylformamide, dimethyl acetamide, N-methyl pyrrolidine and acetonitrile.

The Lewis acids used in this are selected from cationic resins,para-toluene sulfonic acid, aluminium chloride, etc.

The temperature at which the reaction may be carried out may vary from25 to 80° C., preferably between 50 to 70° C.

The invention is now illustrated with a few non-limiting examples.

EXAMPLE 1 Step 1. Preparation of10-Methoxy-5H-dibenz[b,f]azepine-5-carbonyl chloride

100 gms of 10 Methoxy iminostilbene is dissolved in 300 ml chloroform &cooled to 0° C. Bis (trichloro methyl) carbonate (BTC) 65 gms is added.67 gms of triethyl amine (TEA) in 100 ml chloroform is added slowly overa period of 6 hour & maintaining the temperature 0-5° C. Temperature isthen increased to 25-30° C. 1 & maintained for 8 hour. The reactionmixture is poured into 300 ml water & layers are separated. Chloroformis evaporated 10-Methoxy-5H-dibenz[b,f]azepine-5-carbonyl chloride isisolated in methanol. Yield obtained is 110 gms (86%) of theoretical.

Step 2. Preparation of 10-Methoxy-5H-dibenz[b,f]azepine-5-carboxamidefrom 10-Methoxy-5H-dibenz[b,f]azepine-5-carbonyl chloride

100 gm of 10-Methoxy-5H-dibenz[b,f]azepine-5-carbonyl chloride isrefluxed in 500 ml methanol. Dry ammonia is passed into the boilingsolution for 2 hours. The methanol is distilled water added and thereaction mixture is cooled to 25-30° C. and filtered. Yield of10-Methoxy-5H-dibenz[b,f]azepine-5-carboxamide is 82 g.

Step 3 Preparation of oxcarbazepine from10-Methoxy-5H-dibenz(b,f)azepine 5-carboxamide

85 gm of 10-Methoxy-5H-dibenz[b,f]azepine-5-carboxamide is dissolved in425 ml of ethylene dichloride. To this 800 ml of 2N o-toluene sulfonicacid is added and heated to 75-80° C. & maintained for bout 3 hours. Itis then cooled to 20° C. & maintained for about 1 hour. The productoxcarbazepine is separated by filtration. This is then purified inacetone-water to yield 55 gms of pure oxcarbazepine.

EXAMPLE 2 Step 1. Preparation of10-Methoxy-5H-dibenz[b,f]azepine-5-carbonyl chloride

100 gms of 10-Methoxy iminostilbine is dissolved in 300 ml chloroform &cooled to 0° C. 65 gms of Bis (trichloro methyl) carbonate (BTC) isadded to the solution followed by the addition of 54 gms of Dimethylaniline in 100 ml chloroform over a period of 4 hours maintaining thetemperature 0-5° C. The temperature is then maintained 0-10° C. &maintained for 2 hours. The reaction mixture is poured into 300 ml water& layers are separated. Chloroform is evaporated & product is isolatedin methanol. Yield obtained is 104 gms (82% of theoretical).

EXAMPLE 3 Step 1. Preparation of10-Methoxy-5H-dibenz[b,f]azepine-5-carbonyl chloride

100 gms of 10-Methoxy iminostilbene is dissolved in 300 ml chloroform &cooled to 0° C. and 45 gms Bis (trichloro methyl) carbonate (BTC) isadded followed by he addition of 45 gms of TEA in 100 ml chloroform overa period of 8 hours maintaining the temperature at 0-5° C. Thetemperature is then increased to 25-30° C. & maintained for 2 hours. Thereaction mixture is poured into 300 ml water layers are separated.Chloroform is evaporated & product is isolated in methanol. Yieldobtained is 100 gms (80% of theoretical):

The present invention obviates the use of phosgene gas in thepreparation of 10-methoxy-5H-dibenz[b,f]azepine-5-carbonyl chloride from10-methoxy-5H-dibenz[b,f]azepine (10-methoxy iminostilbene). Further theinvention provide a process for the conversion of the intermediate10-methoxy-5H-dibenz[b,f]azepine-5-carboxamide to10-oxo-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide (oxcarbazepine)without the use harsh conditions and strong mineral acids therebyobtaining high quality oxcarbazepine in a cost effective manner fromeasily available raw materials.

1. A novel process for preparation of10-oxo-10,11-dihydro-5H-dibenz[b,f] azepine-5-carboxamide(oxcarbazepine) via intermediate10-methoxy-5H-dibenz[b,f]azepine-5-carbonyl chloride, comprising thefollowing steps: a) Preparation of an intermediate10-methoxy-5H-dibenz[b,f]azepine-5-carbonyl chloride, from10-methoxyiminostillbene using bis (trichloromethyl) carbonate (BTC)triphosgene with organic base/organic solvent b) Conversion of aboveintermediate to 10-methoxy-5H-dibenz[b,f]azepine-5-carboxamide usingammonia and with suitable solvent. c) Formation of oxcarbazepine fromstep (b) using Lewis acid in an appropriate organic solvent at asuitable temperature between 25-80° C. preferably at 50to 70° C., d)Isolation using organic solvent,
 2. A novel process as claimed in claim1, wherein at step (a) organic base is slowly added to the solution fora period of 3-24 hrs, maintaining a temperature at 10° C., aftercompletion of reaction, mixture is allowed to rise to room temperature,followed by separation of organic layer, and distilled to get crudeintermediate, purified using organic solvent.
 3. A novel process asclaimed in claim 1 & 2, wherein the ammonia gas is purged till thereaction completion, distilled the solvent, added water, followed bycooling at room temperature to isolate intermediate,
 4. A novel processas claimed in the above claims, wherein the solvent selected is fromchlorinated aliphatic hydrocarbons/aromatic hydrocarbons or aproticsolvent in the preparation of carbonyl chloride,
 5. A novel process asclaimed in claim 4, wherein chlorinated aliphatic solvents are such asmethylene dichloride, chloroform, ethylene dichloride,1,1,1,-trichloroethane, trichloroethylene etc.
 6. A novel process asclaimed in claim 4, wherein the solvent aromatic hydrocarbons areselected from toluene, xylene, chlorobenzene, etc.
 7. A novel process asclaimed in claim 4, wherein the aprotic solvents are selected fromDimethyl formamide, Dimethyl acetamide, N-methyl pyrrolidine andacetonitrile.
 8. A novel process as claimed in claim 1 & 2 wherein theorganic base is selected from aliphatic/aromatic tertiary amines.
 9. Anovel process as claimed in above claims, wherein the molar ratio of10-methoxy iminostilbene to BTC is 1:0.34-0.5, and the molar ratio withbase is 1:1-1.5.
 10. A novel process as claimed in claim 9, wherein thesolvent selected from acetone, methyl cellulose, methanol, ethanol,isopropyl alcohol, dimethylforamamide etc.
 11. A novel process asclaimed in claim 1, wherein the Lewis acid is selected from p-toluenesulfonic acid, cationic resins etc.
 12. A novel process for preparing10-oxo-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide (oxcarbazepine)via intermediate 10-methoxy-5H-dibenz[b,f]azepine-5-carbonyl chloridesubstantially therein described with reference to foregoing examples.